Nanotechnology holds promise for new treatments for disease in man. Nanoparticle-based approaches offer the possibility of significant advances over current clinical methods accommodating multiple therapeutic, imaging, targeting or other effector functions within each nanoplatform. while improving the pharmacological properties of imaging agents and drugs The multifunctional nature of nanoplatforms is therefore well-suited for the diagnosis and treatment of complex diseases involving multiple physiological compartments, such as cancer. The overall objective of project 3 is to characterize the impact of vascular targeting on the accumulation of new programmable "smart" nanoplatforms (SNaPs) within tumors. AIM 1 will examine the characterize how targeting nanoplatforms to oncofetal integrin receptors - expressed on tumors and tumor vasculature - leads to accumulation within these sites. These studies will focus on understanding the impact of affinity and avidity on the ultimate accumulation of nanoparticle within the target site. In AIM 2. we will assess targeting of nanoplatforms which undergo spontaneous self-assembly on a "honeycomb" core, based on host-guest chemical interactions. Assembly is dependent upon integration of polyethyleneglycol polymer (PEG)-conjugated molecular guests. The distal terminus of the PEG polymers are pre-conjugated to "programmable" elements, such as targeting or imaging agents. The targeting and stability of the SNaPs will be tested against conventional nanoparticles. Both AIMS 1 &2 will employ MRI of avian tumor models and the dorsal window preparation of optically imaged mice with dual reporter (optical & Gd) bearing nanoparticles. AIM 3. The capacity to incorporate multiple targeting elements into the SNaPs by simple ratiometric combination of the host platform and the guest-anchored moieties will be used to evaluate whether combinatorial approaches at targeting - using ligands for two different receptors on the target cell - offers any increase in specificity over singly targeted. Finally, in AIM 4. we will extend the studies from simply imaging accumulation at particle sites to testing whether multifunctional, imagable nanoparticles can detect nascent tumors in genetic preclinical models of disease. The studies will employ Optical and MR imaging of mouse models of subcutaneous tumor growth and metastasis, and spontaneous murine models of tumor development. We believe that these studies should lay the groundwork for a new generation of easily programmed, multifunctional nanoplatforms, amenable to the imaging and possibly treatment of malignancy in human patients. Such particles represent an important first step towards the development of "on site" programmable and personalized, but mass-producible, diagnostic/therapeutic products.